Carcinogenesis is a multistage event affected by a variety of genetic and epigenetic factors and is typified by the outbreak of uncontrolled cell growth originated from different tissues. A universal goal for anticancer research lies in the development of a clinical treatment that is highly effective in curtailment of tumor growth, non-toxic to the host, and is affordable for most patients. Drugs that inhibit targets that are unique to dividing cells, particularly cells dividing in an uncontrolled manner, are an ideal paradigm for chemotherapeutic agents, the greater the specificity to cells that are dividing in an uncontrolled manner the lower the risk of attendant side effects.
The inventors and colleagues have previously reported that tetra-O-methyl nordihydroguaiaretic acid (M4N), also known as EM 1421 and terameprocol, a semi-chemically synthesized derivative of nordihydroguaiaretic acid (NDGA) possessed antiviral and anti-cancer activities in cultured cells, in mouse models, and in human xenografts in nude mice. As a transcription inhibitor, M4N suppresses Sp1-regulated cdk expression and causes cell cycle arrest at the G2 phase of the cell cycle.
Sorafenib inhibits the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation. In addition, it blocks tumor angiogenesis via inhibition of tyrosine kinases in the VEGFR-2/PDGFR-beta signaling cascade. It is currently approved for the treatment of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) and is under investigation for use in non-responsive thyroid cancer and glioblastoma. M4N (tetra-O-methyl nordihydroguaiaretic acid) is an Sp1 transcription inhibitor developed in our laboratory that has been shown to act synergistically with the kinase inhibitors UCN-01, rottlerin and LY294002 in the induction of rapid death in human prostate cancer cells.
As such, there still exists a need for novel and synergistic therapies for the treatment of neoplastic diseases.